Scenario Four

Contents

• Risk taking behaviour

• Smoking:
o Effects on the body
o Effects of passive smoking
o Smoking cessation
o Economics of smoking
• Alcohol: hersh
o Metabolism of alcohol (Chinese)
o Alcoholic liver disease
o Liver cirrhosis
• The liver: - hersh
o Gross anatomy and blood supply
o Histology and description
o Physiology and functions
o Carbohydrate metabolism
o Protein metabolism
• Drug metabolism (p450 system) - hersh
• Gall bladder:
o Gross anatomy and blood supply
o Physiology and function
o Diseases of the gall bladder
o Pharmacology associated with gall bladder diseases
o Open and laparoscopic cholecystectomy
• Excessive thrombosis:
o Physiology of thrombosis/clotting
o Disorders of excess thrombosis
o DVT and Virchow’s triad
o PE
o Pharmacology – antiplatelets, anticoagulants and thrombolytics
• Hyperlipidaemia: hersh
o Lipid metabolism
o Statins and fibrates – including economics
• Abdominal wall anatomy and abdominal pressure - hersh
• Anatomy of the groin, femoral triangle and inguinal canal
• Hernias:
o Types and symptoms
o Treatment and surgery
• Pre and post-operative assessments - hersh
• Antibiotics - hersh
• Consent for procedures
• Communication skills:
o Shared decision making
o Explanation and planning
 Risk-taking Behaviour

Important models/terms
• Behavioural theory of motivation – there is “intrinsic” and “extrinsic” motivation – intrinsic motivation refers
to the individual’s personal motivation to carry out a behaviour, whereas extrinsic motivation is that which
incites a person to do something such as cheering on by friends or incentives. Excess of these “motivations” in
risky behaviours can be influential.
• Self-efficacy - this is the belief in oneself that one can perform a particular behaviour
• Need-achievement theory – involves need for achievement, need for power and need for affiliation – all
powerful psychological influences on our activities which can enhance our risk taking behaviour
• Health promotion model – encompasses the reasons for risky health behaviours e.g. alcohol misuse based on a
general theory of motivation – as influenced by psychological empowerment, available information, education,
social groups.

Influences on risk-taking behaviour

• Social group – performing risky behaviours can be a sign of the individual’s ability to perform or endure
something which forms their identity. Risk taking can be part of group-bonding activities. The more risky the
behaviour, the more that it will cement bonds and deter any non-committed group members.
• Culture and religion
• Genetics - genes for cooperative behaviour and willingness to take on costs in groups can be selected for in
evolution. Genes involved in risky behaviour can be selected for by natural selection if there are net benefits to
reproductive success: i.e., the benefits (increased mating success, advantage to group participation) on average
outweigh the costs (physiological costs of injury, death).
• Sex/hormonal – testosterone has been correlated with risky behaviour e.g. smoking and alcohol abuse and also
with thrill-seeking.

The Effects of Smoking on the Body

Physiological effects of smoking

• Cigarette smoke contains: nicotine, tar, carbon monoxide and >4000 other chemicals of which at least 60 are
carcinogenic
• Nicotine – this is a highly addictive stimulant drug (19 seconds to get to the brain).
o MOA: Binds to nicotinic acetylcholine receptors by mimicking acetylcholine, which are ubiquitous in the
brain an autonomic nervous system  stimulate adrenaline release. Also increases the levels of dopamine
(inhibits monoamine oxidase) and beta-endorphin, which can generate feelings of pleasure
o Effects are widespread and include: increase in heart rate, cardiac output, respiratory rate and blood
pressure, atherosclerosis, thrombosis
• Tar – resinous particulate formed when tobacco is burnt. It contains carcinogens and can inhibit ribonucleotide
reductase which aids lymphocyte proliferation and paralyses cilia  increased susceptibility to respiratory
infections.
• Carbon monoxide – binds irreversibly to haemoglobin in red blood cells to form carboxyhaemoglobin which
reduces the “oxygen carrying capacity” of the bloodstream. This can deprive all tissues of oxygen but most
importantly the heart, brain, liver, and in a pregnant woman, to the developing foetus.
• Smoke – irritant to respiratory mucosa  swelling and increased fluid secretion of the mucus glands,
ciliostatic effect, increased number of pulmonary macrophages which attract leukocytes and the release of
elastase, metaplasia of the epithelial cells (epithelial cells lose their cilia, and the lining becomes populated by
cells that can resist chemical irritation and drying).

Addiction and dependence

• Definition: the essence of addiction is not so much difficulty in refraining as failure to refrain despite repeated
attempts. (Heather 1994)
• Addictions are determined by:
o The Person – Some people have more “addictive” personalities than others.
o The Drug – Nicotine is just as an addictive drug as heroin or cocaine.
 o The Situation – You can be programmed to need a cigarette at certain times.
• You are said to be addicted if you have 3 or more of the following signs over a year:
1. Tolerance
2. Withdrawal
3. Attempts to control
4. Time spent on use
5. Sacrifices made for use
6. Use despite suffering

Health effects
• Reduced life expectancy - smoking kills ~114,000 people in the UK each year and reduces life expectancy by
7-8 years; each cigarette shortens a smoker’s life by around 11 minutes
• Cardiovascular disease – smoking is a risk factor for:
o Hypertension
o Stroke, MI, peripheral vascular disease, thrombosis
o Impotence (increases risk of erectile dysfunction by about 50%)
• Cancer:
o 1 in 5 heavy smokers (who smoke >15 cigarettes a day) will die of lung cancer
o Other common cancers: mouth and laryngeal cancer
o Other less common but associated cancers: bladder, oesophageal, kidney, pancreatic, cervical, leukaemia
• Respiratory symptoms:
o More prone to respiratory infections
o Tachypnoea
o Productive cough
o COPD – emphysema and chronic bronchitis in 80% of cases
o Worsens asthma – as it enhances bronchoconstriction and mucus production
• Other health risks:
o Eye: macular degeneration, cataracts
o Mouth ulcers
o Lowers bone density – increases risk for osteoporosis
o Complicated pregnancies – low birth weight babies, premature babies, miscarriage, bleeding during
pregnancy, sudden infant death syndrome (cot death)

Smoking Cessation

The transtheoretical model of change

• TTM predicts a person's success or failure in achieving a proposed behaviour change, such as developing
different habits. Therefore it is central to understanding smoking cessation.
• Individuals move through five stages (precontemplation, contemplation, preparation, action, maintenance) in
the adoption of healthy behaviors or cessation of unhealthy ones
• These phases do not follow a simple linear progression. Relapse is a common and expected occurrence in
addiction recovery - the stages are seen as a set of dynamically interacting components through which the
individual will likely cycle a number of times before achieving sustained behavior change
• This is known as the spiral model of the stages of change movement through the stages is facilitated by
different processes depending on the given stage.

Stages of smoking cessation

• Many people need help stopping smoking because they experience 2 forms of nicotine withdrawal:
1. Behavioural symptoms – requiring advice and support
2. Physical symptoms – requiring pharmacotherapy
• There are 3 levels of support in smoking cessation:
o Level 1 - brief opportunistic advice from health professionals provided during all routine consultations
including: asking about smoking status, advice, assistance to stop smoking and arranging a follow up
appointment. Referral can be made to a smoking cessation clinic.
o Level 2 - moderate support provided by a trained healthcare professional or other person who has been
trained and accredited as a Level 2 Adviser. Support is on a weekly basis over a 4 week period including an
 initial assessment to assess motivation and to agree to a suitable cessation aid with the patient, setting of a
quit date and thereafter weekly contact should be maintained over a 4 week period.
o Level 3 - in depth support provided by specialist advisers who are trained to support smokers in group
settings and one to one consultations (usually reserved for heavy smokers but open to all smokers). Patient
is seen more often in weekly sessions over 7 weeks.

Pharmacological Options
 Research shows that the patient is twice as likely to succeed when using NRT or other products
Nicotine replacement therapy
• Provides nicotine in a slower and less satisfying way than tobacco smoking but is safer and much less addictive
• Types of NRT: patches, gum, lozenges, sublingual tablets, nasal spray, inhalator
• Side effects: nausea, dizziness, palpitations and headaches. Cautioned in CVD as it does have vascular effects.
• Contra-indicated in pregnancy

Bupropion or zyban
• These are antidepressants licensed for smoking cessation
• Treatment is started two weeks before quitting smoking, and it is usually found that after 11 days the patient
will stop smoking of their own accord.
• MOA - zyban might increase levels of noradrenaline and dopamine in the brain counteracting the reductions in
the neurochemicals seen during nicotine withdrawal.
• Contra-indications: increased risk of seizures (including brain tumour, previous head injury, other medications,
diabetes, alcohol abuse), renal impairment, hepatic impairment, elderly, hx of depression, pregnancy

Alternative therapies
Acupuncture, hypnotherapy, St John's Wort, Avena Sativa, Nicobrevin (contains Vitamin C, camomile and
passiflora helps ease cravings, anxiety, irritability, depression, increased appetite and increased catarrh and mucus)

Cost-effectiveness
• Smoking is a big problem – 13million smokers in the UK; responsible for 120,000 preventable deaths each yr
(leading cx of avoidable illness and premature death in the UK). It kills 1 in 2 smokers and worsens current
diseases.
• Costs the NHS £1.7bn a year
• Overall smoking cessation is a cost-effective program - it costs £600-£750 per life year gained – compare that
to statins which cost £4000-£13,000 per life year gained.
• The White Paper “Smoking Kills” in 1998 developed comprehensive smoking cessation clinics across the UK,
which was the first time smokers in the UK, were offered some form of support.

Alcohol

Metabolism of alcohol
• Most alcohol (more than 80%) is metabolised by alcohol dehydrogenase pathway
• Less than 20% is metabolised by microsomal enzyme (P450) oxidising system by the specific enzyme
CYP2EI, which is induced by ethanol

1. Alcohol in the gut is absorbed and passes via the portal vein to the liver
2. Ethanol (alcohol for this purpose) encounters alcohol dehydrogenase a cytoplasmic enzyme which performs
the following, reversible reaction

3. Then another cytoplasmic enzyme aldehyde dehydrogenase performs the irreversible reaction. This all requires
a continuous supply of NAD

4. When excess ethanol is consumed, acetaldehyde spills out into the blood stream causing headache, nausea
and vomiting.
5. Normally a thiokinase enzyme converts acetic acid into acetyl CoA. This pathway is unremarkable but if there
is ethanol excess then interactions with other metabolic pathways occur

Factors affecting alcohol metabolism

• Food in stomach
• Sex
• Body fat
• Ethnicity - many East Asians (e.g. about half of Japanese) have impaired acetaldehyde dehydrogenase; this
causes acetaldehyde levels to peak higher, producing more severe hangovers and other effects such as flushing
and tachycardia.
• Pre-existing liver disease
• Drug interactions – the rate of alcohol detoxification can be slowed by drugs that interfere with the action of
alcohol dehydrogenases: aspirin, fumes of certain solvents, many heavy metals, and some pyrazole
compounds. Also suspected of having this effect are cimetidine, ranitidine, and paracetamol (overdose)

Ethanol overload
• The effects are all due to lowered levels of NAD and increased levels of NADH
• Ethanol excess leads to hypoglycaemia because above a certain concentration ethanol (10mM) inhibits the
reversible reaction with alcohol dehydrogenase
• Physiologically this isn’t much alcohol since 200ml of sherry (3 glasses) produces blood alcohol in excess of 7
mM and levels can remain between 5-10 mM for 2 hours

• Gluconeogenesis is inhibited by inhibition of enzymes requiring NAD

• Since this is the first step in committing lactate to glucose formation then gluconeogenesis is inhibited

Other effects of alcoholism on liver

• Vit A (retinol) is also an alcohol. Conversion of it to retinal causes night blindness symptoms

• The same reaction is effected during spermatogenesis in the testis

Alcoholic liver disease

• Facts and figures:
o 8% of Europeans and North Americans are excessive drinkers – approximately 25% of liver cirrhosis is
due to alcohol.
o £2 billion lost to British industry per year owing to the effects of alcohol; in the US it is >20x this amount
• Aetiology: excess alcohol consumption, genetic susceptibility, ↓action of alcohol dehydrogenase e.g. Asians,
women, lean people, young drinkers, pre-existing liver disease e.g. chronic viral hepatitis, haemochromatosis
etc
• Pathological features – there are 3 main presentations:
1. Fatty change – alcohol metabolism invariably causes hepatic fatty acid synthesis and reduced fatty acid
oxidation especially in zone 3. Cell cytoplasm gets filled with fat droplets  swelling with fat (steatosis)
similar to that seen in obesity, diabetes, starvation, pregnancy and chronic HepC infection. Eventually
there is fatty destruction of the hepatocyte. Steatosis is almost always present in heavy drinkers (>80g of
alcohol per day for >5 years); it disappears on stopping alcohol.
2. Alcoholic hepatitis – there is infiltration by polymorphonuclear leucocytes, hyaline material (Mallory
bodies) and giant mitochondria are seen, with consequent hepatocyte necrosis mainly in zone 3 of the liver.
Mallory bodies are suggestive of alcoholic liver disease, but they are also seen in other liver disease e.g.
Wilson’s disease and PBC.
3. Fibrosis/cirrhosis – sometimes collagen is laid down around the central hepatic veins (perivenular fibrosis)
- fibrosis initially develops adjacent to sinusoids and then bridges between central veins and portal tracts.
This can progress to cirrhosis, which is a generalised fibrosis and nodule formation. Alcohol also directly
 causes cirrhosis by transforming stellate cells into collagen-producing myofibroblast cells. Cirrhosis may
then develop if there is an imbalance between degradation and production of collagen.
• Clinical features:
o Vague sx: nausea and vomiting, abdominal pain, and diarrhoea (due to the alcohol or its withdrawal)
o In extensive hepatocellular damage: jaundice, ascites, ankle oedema, fever, hepatosplenomegaly,
significant abdominal pain.
o Signs of liver cirrhosis and its complications
• Investigations:
o Alcohol consumption in units (<28/wk for men; <21/wk for women)
o CAGE questionnaire to determine patient alcohol consumption. 3 or 4 positive answers suggests a high
probability of alcohol abuse or dependency:
1. Have you ever felt that you should Cut down your drinking?
2. Have people Annoyed you by criticising your drinking?
3. Have you ever felt Guilty about your drinking?
4. Have you ever had an Eye-opener – an early morning drink to steady your nerves or help a hangover?
o Blood tests: FBC and LFTs (raised bilirubin, raised AST and ALT, raised AlkPhos, high PT, low serum
albumin, raised GGT – in alcoholic hepatitis)
o Imaging of the liver: ultrasound or CT will show any fatty infiltration
o Liver biopsy is the gold standard
• Treatment:
o Conservative: stop drinking, tx withdrawal sx with benzodiazepines, multivitamins (vitamin B complex,
high protein and calorie supplements), IV thiamine to px Wernicke-Korsakoff encephalopathy
o Fatty liver – cessation of alcohol consumption will make the fat disappear from the hepatocytes
o Alcoholic hepatitis – in severe cases mortality is 50%+. Try: rest, tx encephalopathy and ascites, feed
patient via an NG tube or IV and vitamins B and C should be given by injection, corticosteroids and
antifungal prophylaxis
o Alcoholic cirrhosis – advanced cirrhosis  5-year survival rate falls to 35%. Requires liver
transplantation.

Anatomy and histology of the liver

Gross anatomy
• The liver is the largest gland in the body weighing around 1.4Kg.
• The liver consists of two major lobes (right and left) externally divided by the falciform ligament. The
falciform ligament helps tether the liver onto the anterior abdominal wall.
• Two minor lobes called the quadrate and caudate lobe can also be found. They are separated from the major
lobes by fibrous remnants of foetal veins and the gall bladder
• The ligamentum teres (formerly the umbilical vein) delineates the quadrate lobe from the left lobe and gall
bladder as it passes cranially attaching the liver to the diaphragm. The fissure from the ligamentum venosum
on visceral (caudal) surface separates the caudate lobe from the left lobe (essential clinical anatomy page 117).
• Vessels and nerves
o The porta hepatis on the inferior surface (figure 1C) is the site where various vessels nerves and ducts
enter and exit the liver.
o The hepatic portal vein (supplies 70%) and hepatic artery (supplies 30% of blood). they enter here
forming a dual circulation
o The hepatic nerve plexus the largest derivative of the celiac plexus enters here
• The hepatic ducts right and left, exit here
• The lymphatic vessels exit here to drain into the celiac nodes as they retrace the arterial supply.
• The common hepatic duct is joined by the cystic duct which will empty into the duodenum at the duodenal
papilla (or ampulla of Vater) in union with the pancreatic duct.

On the cranial aspect, the bare area (shaded purple on figure 1 b) of the liver, so called because of its lack of
peritoneal covering, lies in direct contact with the diaphragm.
Through this bare area the hepatic veins formed from the union of hepatic central veins exit the liver. These
hepatic veins unite and drain into the IVC inferior to the diaphragm. This venous union also helps hold the liver in
position.
Histology (liver lobule and acinus)
The liver is covered by a connective tissue
capsule which also sends slips of
connective tissue into the liver which
branch extensively forming a network
called septa.

• The septa not only support the liver

but divide the liver into roughly
hexagonal shaped lobules.
• At the centre of each lobule a central
hepatic vein is found which eventually join with other central veins to form the hepatic veins
• Collectively a hepatic artery, vein and bile duct are called a portal tract or triad

• As seen above hepatic cords radiate outwards from the central vein. These are “cords” of hepatocytes.
• Between the hepatocytes are blood filled hepatic sinusoids
• Hepatic sinusoids have an extremely thin and sparse layer of
endothelial cells which is interrupted by populations of
kupffer cells (hepatic macrophages) and Pit cells that are
believed to function as natural killer cells
• The cytoplasm of the endothelial cells contains holes called
fenestrae which allow free movement of blood from inside the
sinusoids to outside the sinusoids
• There is no basement membrane under the endothelial layer
instead the endothelial cells are separated from the underlying
hepatocytes by the space of disse.
• Within the space of disse are peri-sinusoidal cells known as ito
cells which contain vitamin A and are believed to belong to the
fibromyoblast family since they secrete extracellular matrix.
• Hepatocytes have clefts with a central lumen between each cell
representing the bile canaliculus
• This tight association stops bile from leaking and damaging the
liver
• The green spoke-like projections represent the canalicular
microvilli, important in maximising the surface area into which bile
is secreted
• The bile ductules coalesce to form intra-hepatic bile ducts, extra-
hepatic bile ducts and eventually the right and left hepatic ducts
• The lobule is an anatomical separation but a liver acinus is the
basic functional unit of the liver
• AN acinus is dependent on perfusion from a single portal triad
• Depending on the distance of a hepatocyte from the portal triad
there is preferential perfusion to hepatocytes closest to the triad
which means those in zone III are most susceptible to ischemia
• Zone I show greatest metabolism and highest concentration of
oxygen, amino-acids, insulin and glucagon
• Zone 3 is richest in enzymes involved in detoxification (mixed
function oxidases and therefore are most susceptible to drug toxicity

Physiology of the liver

Functions of the liver

1. Exocrine (digestive) function
• Synthesis and secretion of bile salts
2. Endocrine function
• Secretion of insulin-like growth factor (IGF-1) in response to stimulation by growth hormone
• Activation of vitamin D
• Synthesis of triiodothyronine (T3) from thyroxine (T4) (deiodination)
• Secretion of angiotensinogen (catalysed to angiotensin I by renin)
• Metabolism of hormones
• Secretion of cytokines
3. Clotting
• Synthesis of plasma clotting factors (inc. prothrombin and fibrinogen)
• Production of bile salts which are essential for absorption of vitamin K used to produce clotting factors
4. Plasma proteins
• Synthesis and secretion of plasma albumin, acute phase proteins, hormone-binding proteins, binding
proteins for trace elements and lipoproteins
5. Organic metabolism
• Metabolism, detoxification or inactivation of endogenous compounds (e.g. steroids and other hormones)
• Conversion of plasma glucose into glycogen and triglycerides
• Conversion of plasma amino acids into fatty acids (may be incorporated into triglycerides)
• Synthesis of triglycerides and their secretion as lipoproteins/phospholipids
• Glycogenolysis (production of glucose from glycogen) and gluconeogenesis and the release of this glucose
into the blood
• Conversion of fatty acids into ketones (for use by CNS during fasting)
• Production of urea (end product of protein/amino acid catabolism) and its release into the blood
6. Cholesterol metabolism
• Synthesis of cholesterol and its release into the blood
• Secretion of plasma cholesterol into the bile
• Conversion of plasma cholesterol into bile salts
7. Excretory functions
• Secretes bilirubin and other bile pigments into bile
• Excretion of endogenous and foreign organic molecules via bile
• Biotransformation of endogenous and foreign organic molecules
• Destruction of old erythrocytes
8. Detoxification and drug metabolism
• Breakdown of toxic substances and drug metabolism
9. Storage
• Glycogen, vitamin B12, iron and copper
10. Filtration and extraction
• Due to its large vascular supply and abundance of phagocytes (Kupffer cells) the liver can filter the
systemic circulation removing particulate matter (inc. bacteria, parasites, endotoxins and ageing
erythrocytes).
• The products of digested food (inc. carbohydrates, peptides, vitamins and some lipids) are readily extracted
from portal blood by the liver

Synthesis and secretion of bile salts

• Bile is derived from the metabolism of cholesterol and is the only mechanism by which cholesterol is lost
• As it flows along intra-hepatic bile ducts it is modified by duct epithelium to a watery bicarbonate rich fluid
• This may be released or stored in the gall bladder
• Bile synthesis is stimulated by bile salts, secretin, glucagon and gastrin
• The primary bile acids are cholic acid and chenodeoxycholic acid
• In the intestine the primary bile salts are modified by gut flora to the secondary bile acids deoxycholic acid
and lithocholic acid. Because bile salts are amphipathic (that is they have both hydrophobic and hydrophilic
regions) they form micelles facilitating the absorption of fats
• Bile secretion can be bile acid dependant where secretion depends on the rate at which reabsorbed bile salts
are returned from the small-intestine to hepatocytes via the portal circulation. The second mechanism is bile
acid-independent where bile salts, sodium and water, passively follow bicarbonate ions and chloride ions into
the bile ducts
• Bile also contains bile pigments, phospholipids (especially lecithin) and mucus.

Composition of bile:
1. Bile salts (aka ‘bile acids’) (synthesised in the liver and used to make fat soluble in the small intestine, i.e. act
as surfactants or detergents)
2. Lecithin (phospholipid) (synthesised in the liver and used to make fat soluble in the small intestine)
3. Bicarbonate ions and other salts (produced by epithelial cells lining the bile ducts and used to neutralise gastric
acid in the duodenum)
4. Cholesterol (extracted from the blood excreted by bile)
5. Bile pigments and small amounts of other metabolic end products (extracted from the blood excreted by bile)
6. Trace metals (extracted from the blood excreted by bile)

Bile salts are reabsorbed in the ileum via specific sodium-coupled transporters, returned to the liver via the
portal vein. 5% of bile is lost in faeces but new bile salts are synthesised by the liver via oxidation of cholesterol,
then conjugated (with glycine to form glycocholate or taurine to form taurocholate) and stored in the gallbladder.
The liver synthesizes 800 mg of cholesterol per day and 50% is used for synthesising bile salts. Bile salt secretion
is controlled by feedback mechanisms which measure plasma concentrations of bile salts so a greater plasma
concentration causes increased bile salt secretion by the liver.

Bilirubin metabolism
• Normally 80% is generated from old RBC which are broken down by the reticuloendothelial system
• 20% comes from catabolism of haem-containing proteins (e.g. cytochromes and myoglobin) and ineffective
erythropoiesis
• Haem is oxidatively cleaved to biliverdin then bilirubin
• Since bilirubin is hydrophobic it is transported bound to albumin
• Unconjugated bilirubin is delivered to the liver where it is conjugated by UDP-glucoronyl transferase (in the
smooth endoplasmic reticulum) to produce water soluble products suitable for biliary excretion
• Conjugated bilirubin is then secreted into bile canaliculi by active transport. It flows with bile into the small
intestine where it is de-conjugated or metabolised to urobilinogen by gut flora
• Conjugated bilirubin is not reabsorbed although some urobilinogen is
• Faecal urobilinogen gives stools their colour

Metabolism of drugs and waste compounds

The liver is responsible for the metabolism and detoxification of endogenous and exogenous compounds. Some
compounds (proteins) when taken up by hepatocytes are completely digested within lysosomes. Other compounds
especially foreign substances need to be metabolised into “biologically manageable” substances before they
can be excreted. This process is called biotransformation and is composed of two phases. The enzymes necessary
for this detoxification are located in the hepatocytes endoplasmic reticulum in microsomes.

Phase 1 involves oxidation or reduction (commonly oxygenation) to make the compound “react-able” and this is
achieved largely by the P-450 cytochromes. For example a phase 1 reaction may create a hydroxyl group on a
compound. The end result is to make the compound polar.

Phase 2 reactions increase water solubility by conjugating the now “reactive substance with a highly hydrophilic
compound such as glutathione. This new water soluble compound (metabolite plus glutathione) now can enter the
circulation and be removed by kidney filtration. Bilirubin metabolism is an example of phase 2 metabolism.

In summary phase 1 add or expose a functional group which makes it reactive for phase 2 enzymes to make
it water soluble and excretable.

Carbohydrate metabolism

Hepatocytes synthesise glucose in their endoplasmic reticulum (ER) from amino acids and lactate
(gluconeogenesis), or converted from dietary fructose and galactose, or from the breakdown of glycogen stores
(glycogenolysis). Glucose exits the ER and hepatocytes via glucose transporter (GLUT) facilitated diffusion.
Type of glucose transporter Function/distribution
GLUT-1 Basal and non-insulin-mediated glucose uptake by cells
GLUT-2 Important in β-cells for glucose sensing
GLUT-3 Non-insulin-mediated glucose uptake in the brain
GLUT-4 Insulin-stimulated glucose uptake into adipose & muscle

Production of proteins (esp. albumin)

The liver is responsible for the production of many proteins (15-50g/day) that are exported into the blood plasma.
The liver produces plasma proteins that are responsible for maintaining colloid osmotic pressure, clotting factors
responsible for haemostasis, carriage proteins responsible for transportation, pro-hormones and lipoproteins for
signalling. Amino acids used in protein synthesis are absorbed from the GI tract and transported to the liver via
portal blood – hepatic absorption occurs with the aid of ion-coupled transporters. Amino acids are either used
immediately or broken down (deamination, with production of urea).

The healthy liver produces soluble human serum albumin which is the most abundant protein in human blood
plasma. Albumin is synthesised in hepatocytes as preproalbumin which is cleaved before being released from the
rough endoplasmic reticulum. The product, proalbumin, is in turn cleaved in the Golgi vesicles to produce albumin
ready for secretion. The function of serum albumin is to maintin ocotic pressure, buffer pH, transport hormones
(e.g. thyroid hormones), transport free fatty acids, transport unconjugated bilirubin, transport drugs and bind
calcium ions.

Synthesis of Cholesterol
The synthesis of cholesterol is a multi-step process with acetyl CoA as a starting point and involving the enzyme
HMG-CoA. Cholesterol synthesis is inhibited by dietary intake and fasting (and statins) or increased with bile
drainage/obstruction.
Insulin-like growth factor (IGF-1)
IGF-1 is a polypeptide endocrine hormone produced primarily in the liver in response to stimulation by growth
hormone. It plays an important role in childhood growth and continues to have anabolic effects in adults. The
action of IGF-1 is mediated by binding to specific IGF receptors present on many cell types in many tissues.

Activation of vitamin D
There are several forms of vitamin D with the two major forms being vitamin D2 (ergocalciferol, not produced in
the body but absorbed from food) and vitamin D3 (cholecalciferol, made in the skin when 7-dehydrocholesterol
reacts with UVB radiation from sunlight)

The functions of vitamin D include

• Regulation of plasma calcium and phosphorus levels by promoting their absorption from food in the
intestines, and by promoting re-absorption of calcium in the kidneys.
• Promoting bone formation and mineralization
• Inhibition of parathyroid hormone secretion from the parathyroid gland.
• Promoting immunosuppression, phagocytosis, and anti-tumour activity.

Vitamin D is a steroid pro-hormone (no hormone activity itself) that is converted in the liver and kidney to its
physiologically active form 1,25-D. Upon release into the circulation it is bound to a carrier protein in the plasma,
vitamin D binding protein (VDBP) and transported to various target tissues. 1, 25-D mediates its biological effects
by binding to the vitamin D receptor (VDR) found in the nuclei of target cells.

Liver function Tests

Tests of function
Albumin is a major liver product whose concentration depends on nutrition, synthesis in liver and loss (e.g.
nephrotic syndrome)
• Normal level 35-50g/L

o Low albumin is indicative of poor prognosis in liver disease

o Indicates poor hepatocyte function

o Alcohol intake decreases albumin synthesis

o ½ life of 17-26 days so low levels indicate lasting hepatic dysfunction

o Is a negative acute phase protein

PT and INR depend on the speed of coagulation which reflects activity of the vitamin K dependant clotting factors
(2, 7, 9 and 10). They are synthesised in the liver and fall in the presence of significant liver disease
• PT assesses activity of coagulation factors

• INR is the ratio between the clotting time of “normal”: patient in question, normal value is 1 (+/- 0.2)

• Clotting factors have a short half life therefore abnormalities develop quickly (hrs in fulminant liver
failure)

• Cholestasis causes fat soluble vitamin malabsorption which increases INR reversed by administering
vitamin K

• INR doesn’t necessarily reflect severity of liver disease because it can be normal or near normal in
cirrhosis

Tests of liver injury

Transaminases leak into the circulation when hepatocytes are traumatised by injury or undergo frank lysis. Non-
hepatocellular disease can also raise transaminase levels i.e. cholestasis, shock, cardiac failure. Persistent elevations
indicate significant liver disease. Treatable disease can be identified before symptomatic end stage liver failure
ensues.
• Alanine amino transferase (ALT) is liver specific
• Aspartate amino transferase is found in liver, skeletal muscle, myocardium, kidney, pancreas and RBC
o Viral injury causes ALT > AST
o 2 times higher AST than ALT usually indicates alcoholic liver disease
o In cirrhosis the ALT: AST is unhelpful

• Alkaline phosphatase (ALP) is found in the biliary membrane of hepatocyte therefore is raised in
cholestasis and cell injury
o ALP may be elevated in isolation in congestive cardiac failure or lymphoma
o It is also found in bone, intestine, kidney and placenta so consider these in absence of liver findings

• Gamma-glutamyl-transferase (GGT) is a membrane bound enzyme and thus is nonspecific for hepatocyte
injury
o Is also found in the pancreas kidney, intestine and prostate
o Is most useful in conjunction with a raised ALP to confirm cholestasis and rule out e.g. bone origin
of ALP
o Isolated increases are seen in obesity, drug ingestion and alcohol excess
o GGT is prognostic in alcoholic liver disease but not all alcoholics show a rise
o It is increased in biliary disease, pancreatitis, obesity, hyperlipidaemia, diabetes, hyperthyroidism,
porphyria, MI, liver disease in general and enzyme inducing drugs (tricyclics, barbiturates,
anticonvulsants.
Liver cirrhosis
• Cirrhosis = necrosis of liver cells with subsequent fibrosis and nodule formation. This causes disruption to the
architecture of the liver such that blood flow through the liver and its function is affected. It is the end-stage of
any progressive liver disease.
• Aetiology: alcohol, hepatitis B/D/C, and others (e.g. biliary cirrhosis, autoimmune hepatitis, hereditary
haemochromatosis, Wilson’s disease)
• Pathogenesis
o Chronic injury to liver  inflammation  necrosis  fibrosis and regeneration  nodule formation.
o The process of fibrosis is initiated by two main types of cells: stellate cells and kupffer cells.
o Stellate cells are the most important in fibrosis and on activation they become swollen and lose retinoids
with upregulation of receptors for proliferative and fibrogenic cytokines e.g. platelet-derived growth factor
(PDGF) and transforming growth factor β1.
o The normal matrix is replaced by collagens (particularly collagen type I and type III) and fibronectin.
o When the fibrosis extends to become subendothelial fibrosis, there is loss of endothelial fenestrations
which impairs liver function.
o Usually collagenases are released which break down the collagen, but these are inhibited in liver cirrhosis
by increased levels of tissue inhibitors of metalloproteases  worsening of fibrosis.
o There are two types of cirrhosis:
1. Macronodular – there are large, regenerating nodules (>3mm). Seen due to chronic Hep B or C infection.
2. Micronodular – small nodules (<3mm), uniformly affects the liver. Seen with ongoing alcohol abuse.
• Clinical features
o Cirrhosis is asymptomatic. Symptoms arise due to either the underlying disease or when complications of
cirrhosis develop.
o Signs of chronic liver disease: hepatomegaly and/or splenomegaly, ascites, dilated and engorged umbilical
veins called caput medusae, stigmata of chronic liver disease (anaemia, clubbing, leuconychia (due to
hypoalbuminaemia), jaundice, spider naevi, xanthomas, palmar erythema, endocrine features – hair loss,
testicular atrophy, gynaecomastia, amenorrhoea, loss of libido, neurological features – hand flapping
(associated with hepatic encephalopathy), drowsiness, confusion, fetor hepaticus, constructional apraxia)
• Management
o Correct underlying cause
o Requires liver transplantation
o 6-monthly ultrasound to detect the development of a hepatocellular carcinoma
o Treat complications is as follows:
o Ascites  Reduce dietary sodium (allows reabsorption of ascitic fluid), exclude any bacterial
infection, diuretic therapy (increases renal excretion of sodium) – often spironolactone is used because
this is an aldosterone antagonist and often hepatic dysfunction causes hyperaldosteronism. Shunts can
be inserted for persistent ascites.
o Hypovolaemia  salt-poor albumin or plasma expanders
o Hepatic encephalopathy  laxatives, low protein diet (reduces nitrogenous waste which exacerbates
encephalopathy).
• Course and prognosis - extremely variable. Any complications will worsen the prognosis. The 5-year survival
rate is ~50% but this varies depending on the aetiology and stage at which diagnosis is made. The Modified
Child’s-Pugh Classification has been introduced however, which gives a better idea of prognosis.

Complications of cirrhosis
1. Portal hypertension
• Blood pressure in the hepatic portal vein is >12mmHg
• Other causes:
o Prehepatic: portal vein thrombosis, splenic thrombosis, extrinsic compression
o Intrahepatic: cirrhosis, alcoholic hepatitis, schistosomiasis
o Posthepatic: Budd-Chiari syndrome, veno-occlusive disease, right heart failure, constrictive
pericarditis
• Pathophysiology:
o There are 2 main reasons: 1) increased vascular resistance to portal blood flow secondary to cirrhosis
(architectural disorder and active contraction of myofibroblasts, activated by stellate cells and vascular
smooth muscle cells of the intrahepatic veins) and 2) increased portal blood flow secondary to
splanchnic arteriolar vasodilatation due to excessive release of endogenous vasodilators.
o When the pressure rises above 12mmHg, the compliant venous system dilates and porto-systemic
collaterals develop causing “shunting” of blood at points of porto-systemic anastomosis.
o Varices develop at the gastro-oesophageal junction, rectum, left renal vein, the diaphragm, the
retroperitoneum and the anterior abdominal wall via the umbilical vein. Where the left gastric and
short gastric veins anastomose with intercostal and oesophageal veins  gastro-oesophageal varices.
• Sx: often asymptomatic. There is splenomegaly, ascites, peripheral oedema and caput medusae. May be
haematemesis if variceal bleed.
• Tx: tx the underlying cause and tx varices, try TIPS

2. Variceal haemorrhage
• Seen in up to 70% of cirrhotic patients
• Caused by portal hypertension
• Patients present with an acute GI bleed  maleana or haematemesis.
• Tx: aims: resuscitation, restoration of haemodynamic stability and arrest of the variceal bleed. Once this is
done then preventive measures can be started because there is an 80% risk of recurrence.
o Initial treatment – plasma expanders/crystalloids, correct any coagulopathy with vit K, FFP or
cryopreciptate.
o Drug treatments – vasoconstrictors (Octreotide) to cause splanchnic vasoconstriction and restrict
portal blood flow. Vasopressin with GTN – vasopressin encourages the kidneys to conserve water 
increasing plasma volume, but also increases blood pressure therefore the GTN helps to reduce the
peripheral vasoconstriction and also has an additive effect in lowering portal pressure. Beta-blocker
e.g. propanolol +/- a long-acting nitrate.
o Preventative measures:
1. Sclerotherapy - urgent endoscopy and injection of a sclerosant in or around the varices to cause an
inflammatory obliteration.
2. Elastic band ligation - causes thrombotic obliteration.
3. Balloon tamponade – an inflatable balloon is passed into the stomach and the balloon is inflated
with air. Traction on the balloon is maintained for 12 hours until the varices have collapsed.
 4. Transjugular intra-hepatic portocaval shunt (TIPS) – if bleeding is not controlled by
endoscopy, a shunt is placed between the systemic and portal venous system to divert portal blood
flow into the hepatic vein to reduce to pressure gradient between portal and systemic circulations.
A guide wire is passed under x-ray control via the internal jugular vein into the hepatic vein and
passes into the liver (a tract is created through the liver parenchyma from the hepatic to the portal
vein with a needle). The tract is dilated and an expandable metal stent is inserted to create an
intrahepatic portosystemic shunt. There is a high incidence of encephalopathy (30%) with this
operation and up to 50% of shunts may occlude by 1 year so the primary role of TIPS is to rescue
failed endoscopy or bridge patients to liver transplantation.

2. Ascites
• Fluid in the peritoneal cavity
• Secondary to 3 factors: 1) sodium and water retention due to arterial vasodilatation brought on by NO
activates the renin-angiotensin system; 2) Portal hypertension that creates the pressure to increase lymph
production and exudation of fluid into the peritoneal cavity; 3) Low serum albumin due to chronic liver
which reduces plasma oncotic pressure
• Clinical features - Abdominal swelling which can accumulate over a few days-weeks with as much as 1.3L
of fluid. There may be some mild, generalised abdominal pain/discomfort. When there is tense ascites,
breathing and eating can be affected.
• Signs - shifting dullness, peripheral oedema, pleural effusion (due to passage of ascitic fluid through
congenital defects in the diaphragm).
• Management:
o Reduce sodium intake - dietary restriction, avoid drugs that contain sodium e.g. antacids, antibiotics
and effervescent tablets, and avoid any sodium-retaining drugs e.g. NSAIDs or corticosteroids.
o Restrict fluid intake
o Diuretics – spironolactone is the drug of first choice starting at 100mg daily. This drug can cause
gynaecomastia so spironolactone should be substituted for amiloride 5-15mg daily.
o Paracentesis is reserved for symptomatic, tense ascites. It is quite a dangerous procedure because as
the ascites reaccumulates, the circulating volume can plummet  hypovolaemia.
o Shunts can be used for resistant ascites

3. Hepatic encephalopathy
• Portal blood bypasses the liver via collaterals allowing “toxic” metabolites such as ammonia or free fatty
acids to pass directly to the brain  encephalopathy.
• Patients become increasingly drowsy and comatose. Chronically the patient has personality and mood
changes, they can become irritable and get slurred speech. Signs include: bad breath and a flapping tremor.
• Treatment: laxatives and defecation and sterilise the bowel

4. Hepatorenal syndrome
• There is cirrhosis, jaundice and renal failure.
• It is thought to be caused by a drop in intravascular volume  activation of the renin-angiotensin system
and vasoconstriction of the renal afferent arterioles  reduced glomerular filtration.
• Other mechanisms for renal failure are implicated such as the use of NSAIDs, diuretic use, excessive
paracentesis.

5. Hepatopulmonary syndrome
• This is hypoxaemia occurring in patients with advanced liver disease. Most patients have no respiratory
symptoms but with more severe disease are breathless on standing.

6. Primary hepatocellular carcinoma

Hyperlipidaemia and lipid lowering drugs

Function of lipids
• Energy derived from fatty acids produced by the breakdown of triglycerides
• Membrane synthesis using phospholipids, glycolipids and cholesterol
• Insulation
 o Heat: Subcutaneous adipose tissue
o Electrical: Myelin (nervous tissue)
• Cell messengers and hormones
o Steroid hormones
o Prostaglandins
o Inositides
• Emulsifiers
o Bile salts
o Cholesterol
The major function of lipid metabolism is to produce energy by oxidising fatty acids and to synthesise lipids as a
storage molecule (lipogenesis). Fats are insoluble in water and are transported in plasma as protein-lipid complexes
called lipoproteins. The complexes have lipid (triglycerides, cholesterol and cholesterol esters) surrounded by a
phospholipid coat. Apoproteins in the surface of the lipoproteins stabilise the particles and act as receptors for the
liver and peripheral tissues to recognise them. There are five major types of lipoprotein (VLDL, IDL, LDL,
nascent HDL and mature HDL in size order largest to smallest) and are separated according to their density and
electrophoretic mobility. Genetic variability and disorders where abnormal apoproteins are produced predispose to
different lipid disorders
Exogenous lipids: Chylomicrons (CM) are released into the circulation as huge lipoprotein particles. They are
rapidly catabolised in the circulation by the removal of fatty acids. The circulating CM binds to lipoprotein
lipase via apo CII; the binding is reversible and repetitive. The continued removal of fatty acids results in the
formation of smaller CM remnants which are rapidly removed from circulation by the liver. Because of this
metabolism, in the fasting state, CM and CM-remnants are not present in blood.
Endogenous lipids: VLDL released from the liver (in association with apo B-100) and the intestine (in association
with apo B-48) are catabolised via the lipoprotein lipase pathway also, resulting in the formation of Intermediate
density Lipoprotein (IDL). IDL is rapidly removed from the circulation by the liver via high affinity receptors on
hepatocytes which recognise apo E; therefore, the concentration is very low in fasting blood. Low density
lipoproteins (LDL) is derived by the two stages process from VLDL via IDL, and its main components, cholesterol
ester and apo B are derived from these precursors. LDL is more slowly metabolised, hence, it has a relatively high
concentration in fasting blood. Approximately half of the circulating LDL is catabolised in peripheral tissues, the
rest returning to the liver. LDL is the main provider of cholesteryl esters for most tissues, for only the liver, small
intestine and skin have substantial rates of local cholesterol synthesis. LDL is efficiently taken up by cells via high
affinity receptors which recognise its Apo B protein; the number of these receptors is regulated by the cholesterol
content of the cell (as is the rate of cholesterol synthesis). These mechanisms are homeostatic, stabilising the
concentration of cholesterol in each cell. In addition to the high affinity receptor, at least two non-receptor
pathways are involved in LDL internalisation, which become especially important when LDL levels are
increased. The ‘scavenger’ pathway occurs in macrophages, and these cells can become lipid-engorged when LDL
levels are increased, forming the so call ‘foam cells’ which can be found in xanthomas and in atheromatous
plaques.
Reverse Cholesterol Transport: This is a term used to describe the process by which cholesterol in peripheral
tissues is delivered to the liver, either for excretion from the body or for recycling. It represents the only means for
the elimination of cholesterol from cells in most tissues of the body and, as a consequence, is fundamental to cell-
membrane homeostasis and normal cell function.

What is hyperlipidaemia?
Range for cholesterol in UK population may be 4.0 - 6.6 mmol/L (or higher) the upper limit will vary depending on
the population studied. European Atherosclerosis Society and British Hyperlipidaemia Association suggest the
upper value for cholesterol should be 5.2mmol/L a level above which (in epidemiological studies) the risk of
ischemic heart disease increases.
The hyperlipidaemia disorders are a common group of abnormalities characterised by elevated serum cholesterol
and/or triglyceride. They may be primary (genetic) or secondary to other metabolic abnormalities. They are
important because of their clinical sequelae, in particular vascular disease. Patients with hyperlipidaemia are
usually identified for the following reasons:
• Personal or family history of premature atherosclerosis
• Cutaneous manifestations (xanthoma, xanthelasma)
• Pancreatitis
• Routine screening
• In association with other disease
The Primary (Genetic) Hyperlipidaemia)
The common forms are polygenic (e.g. polygenic hypercholesterolemia). Familial hypercholesterolemia is an
autosomal co-dominant condition (heterozygosity 1/500 in the UK) due to an abnormal LDL receptor. Familial
hyperchylomicronemia is rare and is due to dysfunction of lipoprotein lipase. Remnant hyperlipidaemia (Broad
beta disease) is also rare and associated with an apo E2 phenotype. Familial combined hyperlipidaemia is due to
increased apo B synthesis. Endogenous familial hypertriglyceridemia is due to excess hepatic VLDL secretion.

Hypercholesterolemia
• Hypothyroidism
• Diabetes mellitus
• Cholestasis
• Drug induced
• Nephrotic syndrome

Hypertriglyceridemia
• Obesity
• Alcohol excess
• Hypothyroidism
• Diabetes mellitus
• Pancreatitis
• Nephrotic syndrome
• Renal failure
• Drug induced - Oestrogens, the contraceptive pill, beta blockers

Secondary Hyperlipidaemia
A number of secondary causes of hyperlipidaemia should always be considered in hyperlipidaemia patients.
Metabolic abnormalities causing hyperlipidaemia are usually evident from history and examination. Major
secondary causes of hyperlipidaemia include:

Classification of primary hyperlipidaemia

Frederickson Type Lipoprotein changes Causes
I CM increased Lipoprotein lipase deficiency
II a LDL increased Familial hypercholesterolemia
II b LDL & VLDL increased HDL may Multiple type hyperlipidaemia
be low Familial hypercholesterolemia
III IDL & CM remnants LDL & HDL Genetic abnormalities of Apo E
low
IV VLDL increased Multiple type hyperlipidaemia
Familial hypertriglyceridaemia
Common ‘polygenic’
hypertriglyceridaemia
V VLDL & CM increased HDL & Multiple type hyperlipidaemia
LDL low Familial hypertriglyceridaemia
Lipoprotein lipase deficiency

Lipid Lowering Drugs

• Bile Acid Sequestrants: These drugs are non-absorbable anion-exchange resins hitch block enterohepatic
circulation of bile acids. This leads to increased secretion of bile acids and cholesterol, and increased
synthesis of bile acids. This results in up-regulation of LDL receptors in the liver and increased removal of
LDL from the plasma, with reduction of cholesterol levels. E.g. cholestyramine

• Fibre Acid Derivatives: The exact mode(s) of action of the fibrates remain to be determined but are known
agonists of the Peroxisome Proliferator Activated Receptor α receptor (PPARα) in muscle, liver, and other
 tissues. E.g. fenofibrate. Studies show it is effective in combination with a statin but not as a monotherapy.
Activation of PPAR-α signaling results in:

o Increased β-oxidation in the liver

o Decreased hepatic triglyceride secretion
o Increased lipoprotein lipase activity, and thus increased VLDL clearance
o Increased HDL
o Increased clearance of remnant particles

• HMG Co A reductase Inhibitors: These agents are

specific competitive inhibitors of the microsomal
enzyme HMG Co A reductase which catalyses the
conversion of HMG Co A to mevalonate, a major rate
determining step in cholesterol synthesis. E.g. statins

Cost effectiveness of Statins

• Heart disease (HD) costs NHS £1.6bn per year (2003-2004)
• Someone who has more than 0.6% chance of developing HD will benefit from statin treatment
• Currently only those with more than 3% HD risk yr are given statin
• The cost effectiveness of Statins is £4500/life-year-gained for one year’s treatment. This is in people with 3%
annual risk of HD & £6100 a yr for people at a 1.5% annual risk
• The marginal cost to the NHS of expanding treatment from those at 3% risk to those at 1.5% risk = £12 500 per
life year saved
• This is well within the threshold of £30 000 per life year gained that the NICE seems to use as the amount
they will spend on treatment
HOWEVER, this does not take into account the total total budgetary impact.
• Treating those with a > 0.6% risk is 40% of the pop and treating them all would cost £ 6 billion!! – 10%
of NHS budget
• Even if cost-effectiveness is proven at these risks, treating all eligible patients will blow drugs budget

Possible solutions to this problem

• Over the counter Statins (10mg simvastatin currently allowed)
• Private prescriptions
• Re-allocation of societies resources to health
• Increased use of non-pharmacological interventions

Cost of over the counter drugs

Some drugs have been switched from prescription only to over the counter. This increases patient autonomy and
makes better use of community pharmacists. Cost is one of the factors driving this switch, as it will save the NHS
money. However, the cost of over the counter medication has been recognised as a barrier in patient care,
especially in disadvantaged areas as those that are poorer will not be able to afford the prescriptions.

Ethics of over the counter Statins

Advantages:
• Allows patient specific holistic approach to managing risk
• Allows patients not meeting treatment criteria to benefit from Statins if they wish to
• Broader positive effects for society as incidence of HD will fall as more people take Statins
• At the very least, patients would not be worse off, but it may save NHS expenditure on treating HD
releasing money to spend elsewhere
• Allows those who can afford private prescriptions for Statins to have them, so could also benefit those who
cannot afford them although it increases inequality this is ethically justifiable under the difference
principle (form of inequality whereby all in society gain)
Disadvantages:
• Does not agree with the NHS’s principle “to provide a universal service for all based on clinical need,
not ability to pay” and therefore increasing inequality in healthcare which may be seen as unethical
• Patients would be unmonitored in their treatment so don’t know if it is actually needed or having an effect.
It could also cause side effects
• Pt may not understand its use/action/indication

Other options for statins to decrease cost are to allow practitioners to give patients that would benefit from statin
private prescriptions which raises similar ethical issues to over the counter Statins.

The Gallbladder

Anatomy and physiology of the gallbladder

• The gallbladder is attached to the visceral surface of the liver, covered by peritoneum
• It lies protected, non-palpable deep to the costal margin, level with the lateral border of the rectus sheath and
the tip of the 9th costal cartilage.
• However, when inflamed and enlarged, on deep inspiration, the gallbladder will descend just below the costal
margin level with the tip of the 9th costal cartilage mid-clavicular line.
• It is divided into a more mobile fundus, body and neck, which connects to the cystic duct
• Blood supply is via the cystic artery, a branch of the right hepatic artery

Gallstones
• 30% of the Western world
• Caused by a nidus of organic material, often containing bacteria where precipitation of calcium and cholesterol
takes place. This is enhanced by biliary stasis either due to infection or biliary obstruction.
• Types: There are 3 main types of gallstones: 1) cholesterol stone – 10%, yellow-green, made of cholesterol
secondary to excess cholesterol or lack of bile salts + associations with pancreatitis; 2) Pigment stones – small,
black-brown stones made of bile pigment combined with calcium + seen in cirrhosis, biliary tract infections or
haemolytic anaemias (esp sickle cell anaemia); 3) Mixed stones – constitute 70-90% of stones and mainly
contain cholesterol, bile pigments and calcium.
• Risk factors: the 4 Fs  Fat, Female, Fertile, and Forty
• Symptoms:
o Usually asymptomatic
o Biliary colic + nausea and vomiting – temporary obstruction of the cystic or common bile duct by stone
migration. Epigastric/RUQ pain is often worse on eating esp high fat foods and may radiate to R shoulder.
o Jaundice + cholestatic picture (pale stools and dark urine) that goes away
o Murphy’s sign: elicited by placing 2 fingers on the right hypochondrium and asking the patient to breathe
in  pain and arrest of inspiration as the inflamed gall bladder moves below the costal margin. Test is only
+ve if the same test in the LUQ does not cause pain.
• Treatment
o Leave if patient is asymptomatic
 o Acute episodes: analgesics, anti-emetics, IV fluids, broad spectrum antibiotics (if necessary)
o Surgery: open or lap chole (see other section), ERCP (see other section), stone dissolution/lithotripsy (see
other section)

Acute Cholecystitis
• Acute inflammation of the gallbladder
• 95% of cases are caused by gallstones and stone impaction
• Symptoms: continuous epigastric/RUQ pain, vomiting, fever, gallbladder mass. Jaundice may occur.
• CRP is raised, moderate leukocytosis, mild elevations in serum bilirubin, ALP and AST. Murphy’s sign is
positive.
• Plain abdo x-ray shows gallstones/gas (organisms), abdo US (stones, thickening), and biliary scintigraphy
using technetium derivatives of iminodiacetate – these isotopes are taken up by hepatocytes and excreted into
the bile to show up the extrahepatic biliary tree. Acute cholecystitis will show as a filling defect in the cystic
duct and gallbladder.
• Treatment:
1. Conservative management - Nil-by-mouth, IV fluids, opiate analgesia, IV antibiotics (e.g. cefotaxime)
2. Cholecystectomy – this is usually delayed for a few days to allow symptoms to settle, but then can
usually be done safely.

Cholangitis
• This is an infection of the biliary tree.
• Caused by E. coli most commonly, secondary to bile stasis. (Under normal conditions, the bile within the
biliary tree is sterile)
• Seen in gallstones, following cholecystectomy, benign strictures, post-ERCP
• Clinical features: fever, jaundice, RUQ pain, septicaemic shock in severe cases, esp in elderly.
• Ix: neutrophilia, raised CRP, cholestatic picture on LFTs, positive blood cultures, US picture
• Treatment - high dose broad spectrum antibiotics to cover gram -ve and anaerobic organisms in particular e.g.
cefuroxime 1.5g/8h IV and metronidazole 500mg/8h PR.
• Complications - suppurative (formation or discharge of pus) cholangitis is potentially fatal – requires
drainage.

Cholecystectomy surgery
Indication:
• Patients with symptomatic gallstones

Contraindications:
• Acute gallstone disease
• Fibrosed gallbladder
• Advanced liver disease
• Significant scarring and adhesions from previous surgery
• Abdominal wall infection
• Obesity and significant general anaesthetic risk

Laparoscopic technique:
1. Removal of the gallbladder via a laparoscope and a set of minimally invasive tools which requires a
hospital stay of 5-6d
2. Patient is under general anaesthetic
3. An infra-umbilical incision is made and 3-5L of gas is pumped into the abdomen
4. Exploratory laparoscopy is carried out with a trocar to see with the operation is actually feasible
5. Three more trocars/cannulae are inserted into the abdominal wall:
o A 10mm trocar is inserted between the xiphoid process and umbilicus for dissecting instruments
o A 5mm cannula is inserted into the anterior axillary line beneath the costal margin for ratcheted
grasping forceps
o A final 5mm cannula is sited in the right mid-clavicular line beneath the costal margin for grasping
forceps.
6. The cystic artery and duct are exposed and cleaned before the cystic duct is opened and a catheter and
contrast are introduced into the gallbladder. Visualisation of the stone can be performed via sonography.
 7. The cystic duct and artery are then ligated and the gallbladder dissected out of the hepatic fossa via
diathermy.
8. The umbilical defect is closed, the abdomen irrigated and reinspected for leaks and finally the other trocars
are removed and gaseous escape permitted before all sites are finally sutured.

Complications:
• Bile duct injury (0.5%-2%), retained stone in bile duct, biliary peritonitis, haemorrhage - the cystic and
hepatic arteries and the liver bed are all vulnerable to operative trauma and may bleed heavily, wound
infection or abscess, ascending cholangitis, intraperitoneal abscess in the gallbladder bed and around the
liver and chest infections
• Morbidity rate = 1.6% to 11%
• Mortality rate = 0.08%-0.7%

Open vs lap:
Open
Hospital stay of 5-6d
Back to work in 6mks
Risk of bile duct injury is
LESS (0.2-0.3%)
Laparoscopic
Hospital stay of 2d or even day case
Back to work in 1-2wks
Risk of bile duct injury is HIGHER (0.5%-2%)
Less of a need for opiate analgesia
Reduced risk of chest infection, incisional hernias and
wound sepsis
5% may have to be converted to an open procedure

Alternatives to cholecystectomy
• ERCP - treatment of choice for patients that have choledocholithiasis (stone in bile duct) or those unsuitable
for surgery. An endoscope is passed under sedation and contrast is injected so that x-rays can be taken to show
any stones in the bile duct and gallbladder. A sphincterotomy to cut the muscle between common bile duct and
pancreatic duct is usually performed to allow passage of further stones once the bile duct is free of obstruction.
• Drugs:
o Chenodeoxycholic acid or ursodeoxycholic acid – these are synthetic bile acids which help to dissolve the
gallstones. They also reduce cholesterol production by the liver. Side effects are seldom, but include:
itching and N+V. Tx is only successful if there is a functioning gallbladder and stones are almost pure
cholesterol with a diameter of <10mm. Only 20% of patients are usually eligible. There is also a high
relapse rate.
o Statins
• Shockwave lithotripsy – a shockwave can be directed either radiologically or by ultrasound on gall bladder
stones. Stones have to be <10mm in diameter. The greater the calcium content the less likely the success of the
treatment. Gallbladder has to be intact so that the stone fragments can clear via the cystic duct.

Excessive Thrombosis

Physiology of Clotting
Platelets
• Made in the bone marrow from the fragmentation of the cytoplasm of megakaryocytes
• Approximately 1000-2000 platelets can be made from one megakaryocyte
• Takes ~10 days from differentiation of the haemopoietic stem cell to the formation of a platelet that normally
lives 7-10 days itself
• Thrombopoietin regulates platelet production by binding to a c-Mpl receptor on the megakaryocyte and
increasing their number and rate of maturation. This hormone is released by the liver and kidneys. Platelets
also have receptors for thrombopoietin and will remove it from the circulation as part of a negative feedback
mechanism (hence why in thrombocytopenia, thrombopoietin levels are high)
• Structure – platelets are small (0.5-3um) and discoid in shape. They are characterised by a thick, outer
glycocalyx which harbours many glycoproteins of which GPIa, GPIIa/IIIa are the most important and antigens
known as human platelet antigens. They also contain many storage granules including dense, alpha and
lysosomes. These contain clotting factors (alpha granules) and other procoagulant components e.g. dense
granules contain ADP.

Haemostasis
1. Reflex vasoconstriction limits blood flow to the area
2. Damage to the vessel endothelium exposes collagen to initiate the coagulation cascade
3. Platelet changes:
• Platelet adhesion - platelets adhere to the exposed collagen either directly via GPIa/IIa receptors (arteries)
or indirectly via von Willebrand factor (vWF) (veins). Contact with vWF is made via GPIb receptors.
Subsequent rolling and activation of GPIIb/IIIa receptors means there is binding via these receptors too
creating firm platelet adhesion to the vessel wall.
• Platelet activation – receptor binding and subsequent mediators activate platelets which upon activation,
undergo a change in shape from discoid to a spread-out, flattened platelet with filipodia. This new shape
aids platelet-platelet interaction.
• Platelet aggregation – fibrinogen cross links form between GPIIa/IIIa receptors on the platelets. As
receptor binding occurs more platelets are activated and in turn intrinsic platelet mediators are released
including:
o ADP – promotes platelet activation via a positive feedback mechanism
o Thromboxane A2 – vasoconstrictor and increases platelet adhesive properties by interacting with
cAMP. It lowers platelet cAMP levels  ↑ [Ca2+]  platelet adhesive properties
4. Coagulation cascade: There is a biological amplification system involving a series of serine proteases/enzyme
precursors or clotting factors which ultimately generate thrombin.
• Clotting factors – I (fibrinogen), II (prothrombin), III (tissue factor), V, VII, VIII, IX (Christmas factor), X,
XI, XII (Hageman factor) and XIII.
• There are 3 pathways to the coagulation cascade: the intrinsic pathway and the extrinsic pathway
o Intrinsic pathway is triggered by small amounts of thrombin and begins with a complex between
IXa and VIIa which activates factor X
o Extrinsic pathway is triggered by interaction of membrane-bound tissue factor with VIIa. The
TF:VIIa complex activates factor IX and X.
o Common pathway – X is activated to Xa which forms a large complex consisting of: Xa, Va, PL
and Ca. This activates prothrombin to thrombin. Thrombin activates fibrinogen to fibrin.

Control of coagulation
• Tissue factor pathway inhibitor – made by endothelial cells and accumulates at the site of injury due to local
platelet activation. It inhibits Xa, VIIa, and TF.
• Anti-thrombin – combines with serine proteases via peptide bonds and inactivates them e.g. acts on XIa, Xa,
and thrombin
• Protein C and S – inhibit factors V and VII. Thrombin helps to form these proteins as part of a negative
feedback mechanism.
• Blood flow – rapidly achieves dilution and dispersal of activated factors before fibrin formation has occurred.

Tests of haemostatic function

1. Blood count and blood film

2. Screening tests of blood coagulation
• Thrombin time – sensitive to a deficiency of fibrinogen or inhibition of thrombin usually by heparin or
fibrin degradation products. Diluted bovine thrombin is added to citrated plasma at a concentration giving
a clotting time of 14-16s in normal subjects.
 Disorder: DIC or heparin therapy
• Prothrombin time – measures factors VII, X, V, prothrombin, and fibrinogen. Tissue thromboplastin and
calcium are added to citrated plasma. The normal time for clotting is 10-14s. May be expressed as INR.
 Disorder: liver disease, warfarin therapy, DIC
• Activated partial thromboplastin time (APTT) – measures factors VIII, IX, XI, XII in addition to factors X,
V, prothrombin and fibrinogen. The normal time for clotting is ~30-40s.
 Disorder: Haemophilia, Christmas disease (+ conditions for prolonged PT)
3. Specific assays for coagulation factors
• All factors except the one to be measured are present in the plasma to be tested.
• APTT or PT are used to compare the clotting times between the test plasma and normal plasma (as a
percentage of normal).
• Usually looks for a hereditary deficiency
4. Bleeding time
 • Test of abnormal platelet function including diagnosis of vWF deficiency
• Test involves application of pressure to the arm with a bp cuff, after which small incisions are made in the
flexor surface forearm skin. Bleeding normally stops in 3-8min
5. INR – the ratio of the patient’s PT to a mean normal PT with correction for the sensitivity of the
thromboplastin used. This is calibrated against a primary WHO standard thromboplastin. The target INR is
between 2-3. A high INR means you are likely to bleed.

Acquired causes of clotting

Polycythaemia rubra vera
• This is a myeloproliferative disorder characterised by clonal proliferation of the red blood cell bone marrow
stem cell. It is caused by a JAK2 mutation in the haemopoietic cell. Polycythaemia means an increase in Hb
concentration and red cell count is much higher than normal (platelets and granulocytes may also be raised).
Serum B12 is usually also up because haptocorrin is raised secondary to increased granulocyte production.
• Patients are usually quite old and present with a triad of: hyperviscosity, hypovolaemia and hypermetabolism.
Other notable features:
 Pruritis – especially after a hot bath
 Plethoric appearance
 Splenomegaly (large abdominal mass)
 Gout, peptic ulcers, hypertension
• The aim of treatment is to get the haematocrit at 0.45 and get the platelet count below 400. Patients are
venesected and put on aspirin to reduce clot risk. They are also often given myelosuppressive agents such as
busulfan, phosphorus-32 and interferon.

Essential thrombocythaemia
• Malignant proliferation of the megakaryocyte leading to overproduction of platelets which are often abnormal
and large.
• Patients present with repeated clotting because of the excess platelets, but also with bleeding because the
platelets are defective. The spleen is often enlarged due to repeated infarcts. There is a characteristic burning
sensation in feet and hands called “Erythromelalgia” which can be relieved by aspirin.
• Treatment is with myelosuppressive drugs particularly hydroxyurea and also aspirin.

Antiphospholipid syndrome
• Autoimmune disease characterised by antiphospholipid antibodies (lupus coagulant, anti-cardiolipin and
apolipoprotein H aka beta-2-glycoprotein 1) which cause activation of the coagulation cascade. Lupus
coagulant binds to prothrombin and others to protein C/S.
• Patients present with recurrent clots causing DVT, PE, strokes, TIAs, peripheral ischaemia and a purple skin
rash called livedo reticularis. It is typical that this condition causes complications in the 2nd or 3rd trimester of
pregnancy  foetal death and premature babies. Platelet count is LOW.
• Treatment is with aspirin, or warfarin if there has been previous thrombosis (warfarin is teratogenic).

Inherited causes of clotting

• Factor V Leiden gene mutation – very common (4%) blood clotting disorder where there is a mutation in the
gene encoding factor V (part of the common pathway). It becomes less susceptible to cleavage by activated
protein C  increased risk of coagulation. PCR is required for diagnosis and the APTT is not prolonged when
protein C is added.
• Antithrombin deficiency – Antithrombin inactivates Xa and XIa and thrombin. Thrombin and the other
factors are required to bring about activation of fibrinogen to fibrin and thus a stable clot. A lack of
antithrombin (autosomal dominant) means these procoagulants persist and patients get recurrent thrombi.
Antithrombin concentrates can be given to patients especially during childbirth or surgery.
• Protein C/S deficiency – these proteins inhibit factors V and VIII. They are stimulated in a feedback
mechanism by thrombin (balance system). A deficiency in either protein is usually autosomal dominant and can
cause purpura fulminans, a cutaneous haemorrhagic condition.

Deep vein thrombosis

• Virchow’s triad
 1. Damage to the vessel wall – previous clot, age, smoking, local trauma, atherosclerosis
2. Increased blood coagulability – malignancy, pregnancy, pill, PRV, essential thrombocythaemia, protein C
or S deficiency
3. Stasis of flow – surgery, immobility, heart failure, dehydration
• Presentation - swollen, tender warm leg which may become white (phlegmasia alba dolens) with pulses (in
contrast to the pulseless ischaemic limb). The pt is often slightly pyrexic with fast pulse.
• Wells’ checklist of major and minor clinical criteria, which suggest whether a patient is at low, moderate or
high risk of having suffered a DVT, and which may guide subsequent investigation and management.

Minor criteria Major criteria

• History of recent trauma (within
60 days) to symptomatic leg
• Pitting oedema of symptomatic
leg only
• Dilated, non-varicose,
superficial veins in symptomatic
leg only
• Hospitalisation within previous
6 months
• Erythema
• Active cancer
• Paralysis, paresis or plaster immobilisation of the lower limbs
• Recently bed-ridden for >3 days, or major surgery within the
previous 4 weeks
• Localised tenderness along the distribution of the deep venous
system
• Thigh and calf swollen (should be measured); calf circumference 3
cm greater than on symptomless side, measured 10 cm below the
tibial tuberosity
• Strong family history of DVT (at least 2 first degree relatives)

Diagnosis of DVT
• Clinical suspicion if: previous DVT, cancer or confined to bed. In the leg, unilateral thigh or calf swelling or
tenderness, pitting oedema and the presence of collateral superficial non-varicose veins are important signs.
• Serial compression ultrasound:
o Pros: reliable and practical + non-invasive + can be combined with spectral colour or power Doppler
(Duplex)
o Cons: does not distinguish between acute and chronic thrombi
• Contrast venography:
o Reserved for patients with highly suggestive clinical findings but negative ultrasonography
o Iodinated contrast medium is injected into a vein peripheral to the suspected DVT which permits direct
demonstration by x-ray of the site, size, and extent of the thrombus
o Cons: painful, invasive, risk of contrast reaction and produce induced DVT
• Plasma D-dimer concentration:
o D-dimers are specific degradation products of cross-linked fibrin that are released when the endogenous
fibrinolytic system attacks the fibrin matrix of fresh venous thromboemboli.
o This is not a diagnostic test, a raised level is suggestive, but not conclusive, evidence for a deep vein
thrombosis. Other conditions raising D-dimer concentration include: cancer, inflammation after surgery,
and trauma

Treatment of DVT
1. Conservatives measures:
o Bed rest for 24h with foot elevation by 15-30º and full length graduated compression stockings
o Analgesics
o Then mobilize the pt and encourage regular leg exercises
2. Drug treatments:
1. IV heparin (unfractionated heparin):
 IV heparin – a loading dose of 5000 units followed by 1000-2000units/h by continuous pump infusion.
 Monitor by maintaining the APTT at 2-3 times the upper limit of normal
 Continue infusion until target INR achieved.
2. Or give LMWH heparin subcutaneously – PREFERRED!
 200 anti-Xa units/kg once daily or 100 anti-Xa units/kg twice daily
3. Warfarin:
 Start oral anticoagulation at the same time as heparin (it takes at least 48-72 hours to establish its effect)
 Dose: 10mg on day 1, 5mg on day 2, and then 5mg on day 3. After this the dosage should be adjusted
according to the PT. The usual maintenance dose is 3-9mg/day.
  INR is recommended to be 2.5 for the tx of DVT or PE etc, and 3.5 for recurrent DVT
 Continue for 3-6 months. Where PE or DVT is unexplained, try further Ix and long-term therapy is
recommended.
 Give pt an anti-coagulation booklet to explain nature and side-effects of warfarin!
3. Clot removal or dissolution
o Only used for iliofemoral thrombosis or if the viability of the limb is threatened (or major PE or acute MI)
1. Thrombolytic therapy:
 Give within 6hours after sx, but still beneficial up to 24hours
 Streptokinase is given in a loading dose of 250,000 units followed by a maintenance dose 100,000
units/hr for 12-48hrs
 Recombinant tissue plasminogen activator (rtPA) 100mg IV over 2 hours is an alternative.
2. Thrombectomy

N.B an inferior vena cava filter may be used to provide short-term protection against a PE when DVT in the legs is
diagnosed but anticoagulation is contraindicated.

Prophylaxis of DVT

Prophylactic measures for elective surgery:

• General measures:
o Stop oral contraceptives 6 weeks before the operation
o Weight reduction if grossly overweight
o Patients rendered immobile during a period of in-patient investigation benefit from a spell of 2-3 week
activity before re-admission
o Avoid unnecessary pressure on the calf during surgery
o Graduated thrombo-embolism deterrent (TED) stockings during and after operation or if very high risk try
other calf compression devices - pneumatic, electrical
o Post-op: leg elevation and early ambulation
• Drugs:
o Aspirin prior to admission for surgery
o LMWH – 5000 units 12-hourly pre-op followed by this dosage 8-12hrly for 7 days or until the pt is mobile
o Intravenous heparin or oral warfarin is reserved for patients with prosthetic valves undergoing high risk
operations such as hip replacement, or with a prior history of DVT

Thrombophilia screening:
• Required in pts who have recurrent or spontaneous DVT/PE, thrombosis at a young age, familial tendency to
thrombosis or thrombosis at an unusual site. It is also required in women with recurrent foetal loss
• Screening tests:
1. Blood count and ESR to detect elevation in haematocrit, WCC, platelet count, fibrinogen, and globulins
2. Blood film examination – may provide evidence of myeloproliferative disorder; leucoerythroblastic
features may indicate malignant disease
3. PT and APTT – a shortened APTT is often seen in thrombotic states and may indicate presence of activated
clotting factors. A prolonged APTT not corrected by addition of normal plasma may suggest anti-
phospholipid syndrome.
4. Anticardiolipin and anti-beta2-GPI antibodies
5. Thrombin time and reptilase time
6. Fibrinogen assay
7. Activated protein C resistance test and DNA analysis of factor V leiden
8. Antithrombin
9. Protein C and S

Pulmonary Embolism
• Emboli from a deep vein detaches from a clot and becomes lodged in the pulmonary arterial tree. Particularly
common after a thrombosis of the proximal femoral or iliac veins; less likely if it is confined to the calf veins.
• The emboli vary in size and severity from acute massive (>50% occlusion) to chronic thromboembolic
pulmonary hypertension (repeated small emboli)
• Aetiology – Virchow’s triad (see DVT section).
Symptoms
• Typically a triad of: dyspnoea, tachypnoea (>20) and pleuritic pain. But sx depend on size and severity of the
emboli:
• Acute massive PE:
o Big drop in cardiac output so that the patient collapses with hypotension
o Central chest pain
o Cyanosis
o Tachypnoea
o Engorged neck veins
• Subacute PE:
o Progressive severe dyspnoea develops over a few weeks without obvious cause (dyspnoea even at rest)
o Raised JVP
o Tachypnoea
o Hypoxaemia
• Acute minor PE:
o With pulmonary infarction: pleural pain, haemoptysis, effusion, fever
o Without pulmonary infarction: may be silent, ?dyspnoea, ?fever, hyperventilation

Investigations
• Blood tests: may be fibrin degradation products (D-dimers), may be thrombin-antithrombin III present as
evidence of an intravenous thrombus
• ABGs: low PaO2 due to hypoxaemia and low PaCO2 due to hyperventilation (though there is only ventilation
of an underperfused lung)
• ECG: often normal, may be sinus tachycardia, may see, may see right heart strain with depression of the ST
segment
• Chest x-ray: often normal, may be elevation of a hemidiaphragm, may be areas of linear atelectasis (collapse of
part of the lung), may get small pleural effusion with wedge-shaped opacities. In a massive PE there will be an
area of under-perfusion with few vascular markings
• Pulmonary angiography:
o This is the definitive test, but it is invasive
o A catheter is passed from a peripheral vein e.g. the femoral vein, through the right atrium and right
ventricle and into the pulmonary arteries. Radiocontrast material is then injected. Then a rapid sequence of
x-rays are taken.
o You should see intraluminal filling defects, abrupt cut-off vessels, peripheral pruning of vessels and areas
of reduced perfusion
• Ventilation/perfusion (V/Q) lung scan:
o Human albumin, labelled with a gamma-emitting radioisotope, technetium-99m, is injected intravenously.
These particles impact the pulmonary capillaries and the radioactivity emitted from the lung fields is
detected by a gamma camera, thus outlining the distribution of pulmonary perfusion. This can also be done
after inhalation of radiolabelled xenon.
o A completely normal pattern of perfusion is strong evidence against a PE
o You expect a there to be “cold areas” where there is defective blood flow as there is poor perfusion. There
should not be defects in ventilation. There will be multiple areas of perfusion defects that are not matched
with defects in ventilation – a mis-matched V/Q scan.

Pharmacology - drugs to reduce thrombosis

Anticoagulants
Unfractionated (standard) heparin
• MOA: Potentiates the effect of antithrombin by potentiating formation of complexes between antithrombin and
activated serine protease coagulation factors IXa, Xa, Xia which inactivates them irreversibly. It also inhibits
platelet function.
• Indications: DVT, PE, unstable angina
• Dose and administration: Must be given by injection as it cannot be absorbed by GIT. It can be given as a
continuous intravenous infusion (30,000-40,000 units over 24h). It can also be given as a subcutaneous
injection – this is usually used as prophylaxis against venous thrombosis; dose is ~5000 units 12-hourly
preoperatively followed by the same dose 8-12 hourly for 7 days or until mobile.
• Pharmacokinetics: half life of ~1hr, inactivated by the liver, excreted in the urine. There is massive inter-
subject variability so it is very important that you monitor APTT.
• Side-effects:
o Bleeding – stop the infusion; protamine can inactivate heparin immediately (1mg/100units of heparin)
o Heparin-induced thrombocytopenia (HIT) – HIT type 1 is of no clinical significance; there is a mild
lowering of platelets secondary to platelet clumping. However, HIT type 2 (occurs in 5%) is secondary to
generation of IgG antibody to the heparin platelet factor 4 complex which leads to platelet activation 
fall of >50% in the platelet count 5 or more days after starting heparin therapy. Stop heparin therapy, give
thrombin inhibitors (hirudins or lepirudin).
o Osteoporosis – occurs with long-term therapy (>2m) especially in pregnancy. The drug complexes
minerals from the bones – exact pathology unknown.

Low molecular weight heparins – e.g. tinzaparin, dalteparin, enoxaparin

• MOA: It works mainly by inhibiting factor Xa. It has less of an effect on platelets  lesser tendency to cause
bleeding.
• Indications: it is the treatment of choice for preventing or treating DVT, PE and unstable angina and their
prophylaxis. Also used as prophylaxis in pregnancy (does not cross the placenta).
• Dose: it can only be given once a day in prophylaxis (2000-2500 units in moderate risk patients) or once or
twice a day in treatment (200 anti-Xa units/kg) by subcutaneous injection.
• Pharmacokinetics: greater bioavailability, longer half-life (2x) so it only has to be taken once a day. It has a
predictable response with a fixed dose with 100% bioavailability. The risk of complications that you see with
UFH are reduced by 50% with LMWH.
• Side-effects – same as for UFH, but less common

Warfarin
• MOA: competitive antagonist for vitamin K,  decreased production of the clotting factors: II, VII, IX and X.
• Pharmacokinetics:
 Slow to work – VII levels fall considerably within 24h but prothrombin has a longer plasma half-life and
only falls to 50% of normal at 3 days. The patient is fully anticoagulated only after this period.
 Narrow therapeutic range
 Huge interpatient variation
 97% bound to albumin; the free portion is active.
 Broken down in the liver to microsomes to an inactive water-soluble metabolite that is conjugated and
excreted in bile and partially reabsorbed to be also excreted in urine.
• Administration and dose:
 Warfarin is taken orally because it is well absorbed from the gut.
 Before any warfarin is administered, the INR and LFTs must be assessed.
 A starting dose of warfarin is 10mg given at 6pm on day 1; 5mg on day 2 and 5mg on day 3.
 A maintenance dose anywhere between 3-9mg
 Great individual variation in dose required - a lower dose is recommended for the elderly and those with
liver disease.
 The INR must then be measured on day 3 and day 5. The target INR is one between 2.0 and 3.0 – 2.5 is the
standard expected.
• Indications:
 DVT and PE - it is usual to continue warfarin for 3-6 months; lifelong if recurrent
 Long term therapy for: rheumatic heart disease, AF, prosthetic heart valves and severe thrombophilia
• Contraindications: pregnancy (teratogenic), liver disease
• Interactions:
 By any drug that affects albumin binding or excretion of warfarin or those that decrease absorption of vit K
 Drugs that increase effects: sulfonamides, cimetidine, allopurinol, tricyclic antidepressants, metronidazole,
sulfonamides, thyroxine, quinidine, salicylates, amiodarone. Decreases vit K absorption: antibiotics, laxatives.
  Drugs that inhibit effects: barbiturates, rifampicin, oral contraceptives
• Management of warfarin overdose:
 INR >4.5 without bleeding – stop warfarin for 1-2d and adjust dose according to INR
 INR very high (>8) without bleeding – oral dose of 0.5-2.5mg vit K
 Mild bleeding – INR assessment, drug withdrawal, and subsequent dose adjustment
 More serious bleeding – stop therapy, vit K therapy or infusion of FFP or prothrombin concentrates. Dose of
vitK should be 2.5mg.
• Warfarin and surgery:
 Minor surgery – maintain anticoagulation
 Major surgery – stop warfarin to get INR to <1.5 and LMWH given when INR falls to <2 and continued
until INR is >2 after restarting warfarin

New anticoagulants:
• Ximelagatran – this can be given orally and it works by directly inhibiting thrombin. It has the same efficacy
and safety as warfarin, but no monitoring is needed and it is cheaper because of that. However, there is no long
term data available and it is an expensive drug. Liver toxicity is a major problem.
• Fondaparinux – this is a factor Xa inhibitor

Summary of anticoagulation:
1. Heparin given for immediate effect
2. Warfarin started at same time, but takes 2 - 4 days to become fully effective
3. Heparin stopped once anticoagulant effect of warfarin in therapeutic range
4. Start subcutaneous LMWH on suspicion of DVT or PE (if no significant bleeding risk)
5. Check blood “warfarin level” day 3 and give appropriate warfarin dose
6. Stop LMWH when INR 2 - 3

Antiplatelets

Aspirin
• MOA: cyclooxygenase inhibitor that prevents the production of thromboxane A2 by activated platelets.
Normally the COX-1 enzyme within platelets forms TXA2 in activated platelets. TXA2 leads to further platelet
activation and aggregation. Aspirin binds covalently to COX-1 and inhibits platelet function.
• Dose: A loading dose of 300mg works within few hours (given by paramedic) and the normal maintenance
dose is 75mg once daily.
• Indications: prevention of stroke or MI
• Side effects: GI bleed, intracerebral bleed, also reduces gastroprotective prostaglandin so it can cause peptic
ulcers. The effect of the aspirin is permanent on the existing platelets, because they lack nuclei and thus the
ability to make more COX.

Clopidogrel
• MOA: ADP-receptor antagonist. ADP activates platelets and is stored and released by activated platelets. ADP
stimulates activation and expression of GPIIb/IIIA receptor on platelet surfaces, this increases aggregation.
Clopidogrel is an antagonist of the platelet ADP receptor and so reduces platelet aggregation.
• Modestly superior to aspirin. Alternative if aspirin intolerant and used in more major bleeds.
• Dose:
• S/es: GI bleed, intracerebral bleed, severe neutropenia, thrombotic thrombocytopenic purpura

Dipyridamole
• MOA: phosphodiesterase inhibitor. It increases cAMP levels in circulating platelets which decreases their
sensitivity to activating stimuli.
• Indications: allergy to aspirin and in very high risk patients e.g. those with acute coronary syndromes/coronary
stents.
• S/es: GI bleed, intracerebral bleed

Abciximab, tirofiban, eftifibatide

• MOA: block fibrin binding to the GPIIb/IIIa receptor on platelets which are part of the final common pathway
for platelet aggregation by inhibiting these receptors. They therefore prevent platelet aggregation.
• S/es: severe bleeding, hypotension

Thrombolytics
• Examples: Streptokinase, alteplase (t-PA), urokinase
• MOA: promote activation of plasminogen to plasmin which and hence cause the dissolution of clots.
• Older established agents include: streptokinase (cheapest) and tissue plasminogen activator (tPA). Newer
drugs: reteplase and tenecteplase
• They are indicated in an MI but they need to be given early i.e. within 6 hours.
• Side-effects include: haemorrhage, ~1% serious intracranial bleeds

Abdominal Wall Anatomy

Abdominal wall
• Abdominal cavity extends from the dome of the thoracic diaphragm (T8) to level S1.
• Clinically the area is divided into 9 regions by:
o Two vertical planes - run through midpoint of clavicles
o Two horizontal planes: the transpyloric plane (midway between xiphoid process and umbilicus or level
with the 9th costal cartilage) and the transtubercular plane (midway between the ASIS and the highest point
of the iliac crest)
• Key anatomical landmarks include:
o 9th costal cartilage on right side (L1) = tip of gallbladder
o Level with L3, innervated by T10 = umbilicus
o Bifurcation of aorta (L4) = iliac crest
o Level with S2, innervated by T12 = skin superior to the pubic symphysis

Outer subcutaneous fat and fascia

• Outer abdominal layers include: skin, then planes of subcutaneous fat, then fascia.
• Superficial fascia – layer of fatty, connective tissue. Below the umbilicus it splits into 2 layers:
o Superficial fatty layer (Camper’s fascia) – in men this layer covers the penis and after losing its fat and
fusing with the deeper layer it also covers the scrotum (dartos fascia).
o Deeper membranous layer (Scarpa’s fascia) – thin, membranous layer that contains no fat. It fuses with
the fascia lata in the thigh.

The abdominal muscles

• Function:
o Firm but flexible wall that contains abdominal viscera
o Protection
o Assist quiet and forced expiration by pushing viscera up and hence diaphragm – also used in vomiting and
coughing
o Increased intra-abdominal pressure – childbirth, micturition and defecation
o Flex trunk and some can turn trunk to same side
• Outer protective rectus sheath:
o Tendinous sheath in the midline which is formed by the aponeurosis of the 3 flat abdominal muscles
o Completely encloses the upper ¾ of the rectus abdominis and just covers the lower ¼
o The linea alba can be seen where the opposing sides of connective tissues meet
• There are 4 outer abdominal muscles:
1. Rectus abdominis
• Lies either-side of the midline from the pubis and pubic symphysis to the 5th, 6th and 7th costal
cartilages
• Has 2 or 3 horizontal intersections for strength and support (tendinous int.)
• Blood supply is via the internal thoracic (mammary) artery for its superior portion, and the inferior
epigastric artery anastomoses from below for its inferior portion. This muscle is often used in
reconstruction of the breast after a mastectomy.
2. External oblique - fibres pass down and in, from the lateral aspect of ribs before becoming aponeurotic and
attaching to the ASIS and pubic tubercle
 3. Internal oblique – lies just deep to E.O. Fibres pass up and medially from the iliac crest and lateral 2/3 of
inguinal ligament to become aponeurotic and join the linea alba.
4. Transversus abdominis – fibres run transversely from the lateral edge of the thoracolumbar fascia and deep
surface of lower ribs, iliac crest and lateral 1/3 of inguinal ligament, to become aponeurotic and join with
the linea alba.

The peritoneal cavity

• Divided into a greater and lesser sac - the greater sac accounts for much of the peritoneal cavity and is entered
when the parietal peritoneum is penetrated. The lesser sac is formed by the greater and lesser omenta.
• Peritoneum:
o Lines the abdominal cavity and covers most of the viscera
o Two layers: parietal and visceral peritoneum – the potential space between houses a few mm of fluid to
allow free movement
o Throughout the peritoneal cavity are numerous peritoneal folds that connect organs to each other or to the
abdominal wall. These folds include: omenta, mesenteries, and ligaments.
• Omenta:
o Greater omentum:
 Fatty, peritoneal fold that attaches to the greater curvature of stomach and 1st part duodenum
 Drapes over the transverse colon, jejunum and ileum before looping back on itself to blend with the
mesentery of the transverse colon and posterior abdominal wall
 Carries 2 arteries and accompanying veins - right and left gastro-omental vessels
 Migrates and adheres to inflamed bowel
o Lesser omentum:
 Extends from the lesser curvature of stomach and 1st part duodenum to inferior surface liver
 Forms a hepatogastric ligament between liver and stomach, and a hepatoduodenal ligament between
duodenum and liver
 There is an opening called the epiploic foramen containing the common bile duct, hepatic artery and
portal vein + bounded by IVC, and liver lobes.
• Mesenteries:
o Peritoneal folds that attach viscera to the posterior abdominal wall
o Also provide a path for vessels, nerves and lymphatics to reach viscera
o There are 3:
1. Mesentery – connects jejunum + ileum to wall
2. Transverse mesocolon – connects transverse colon to wall
3. Sigmoid mesocolon – attaches sigmoid colon to wall
• Ligaments:
o Peritoneal ligaments that connect 2 organs to each other or to the abdominal wall
o E.g. splenorenal ligament and gastrophrenic ligament

Lumps in groin

Inguinal Hernia
• One of the most common surgical problems – significant
cause of morbidity and time off work
• Hernia - A protrusion of an organ through the wall that
normally contains it
• 50% of hernia surgery is for indirect inguinal hernias
o 80000 operations a year
o 3% of all adults will require the surgery
o M:F ratio 12:1
o Peak incidence in 60s
o 80% indirect
• 20% bilateral hernias comprise approximately 7% of
all surgical outpatient visits
• M: F 8:1
• Affects 1-3% of young children
 • In men the incidence rises from 11 per 10,000 person years aged 16-24 years to 200 per 10,000 person
years aged 75 years or above
Differentials of groin lump
• Femoral hernia; these are seen in various forms, at simplest as a small swelling in the top of the inside of
the thigh. Alternatively, it may be deflected to appear higher as an inguinal hernia. It is either irreducible or
reduces only slowly with pressure. Most likely to strangulate
• Hydrocele (when differentiating from an inguinoscrotal hernia, note it is possible to get above a hydrocele
on examination transilluminates, no pain
• Spermatic cord hydrocele (cyst filled with dead sperm) painless
• Lymph node swelling discomfort or painless
• Abscess (e.g. psoas muscle)pain
• Testicular Carcinoma painless or uncomfortable
• Saphena varix (gravity dependant as are all varicose veins)painless
• Varicocoele
• Bleeding or pseudo-aneurysm
• Undecended testis (painless)

Inguinal herniae
• The testis originates from abdomen descending into the perineum through the inguinal canal. Normally
most of the processes vaginalis closes before birth, with only the most distal part forming the tunica
vaginalis of the testis

• Indirect herniae leaves abdomen through weakness in transversalis facia to enter a patent processus
vaginalis (lateral to inferior epigastric vessels). It enters deep inguinal ring passing through inguinal canal
exiting at superficial ring entering the scrotum. The sac is formed by the processes vaginalis and is
covered by the three layers of the spermatic cord (60-70% of inguinal herniae are indirect)

• Direct inguinal herniae leaves abdomen via weakness in external oblique fascia. Causes of this weakness
may be due to a dilated superficial ring, narrow inguinal falx (curved fold of peritoneum) or a gap in the
aponeuroses, all found more commonly in older men. The direct hernia passes medial inferior to epigastric
vessels without entering the deep ring. It protrudes through posterior wall of inguinal canal, lying outside
the spermatic cord and remaining uncovered by the cord. It emerges from the superficial ring (rarely enters
scrotum).

• Most herniae are reducible, but try to reduce a strangulated hernia as you may release inflammatory content
into normal viscus

Complications in hernias

• An ‘obstructed hernia’ occurs when the bowel is trapped and obstructed but viable (i.e. still has adequate
perfusion)

• ‘Complete herniation’ occurs when a whole part of an organ protrudes

• ‘External herniae’ protrude to the outside world, whereas ‘internal herniae’ protrude from their normal
compartment to another

• ‘Strangulation’ occurs when the blood supply to an area of bowel protruding in the hernia is blocked and
the area of bowel becomes obstructed. The region becomes ischaemic and can subsequently become
necrotic and gangrenous which increases the risk of perforation of the bowel with ensuing peritonitis.
 • The point at which the sac of peritoneum originates through the weakness in the abdominal wall is
typically the point where ‘strangulation’ of the hernia can occur

Different types of hernias

• Pain at the site depending on cause, visible or palpable lump, vague symptoms relating to pressure on an
organ which has become "stuck" in the hernia, sometimes leading to organ dysfunction.

• become more prominent when coughing, straining, or standing up

• Conditions which chronically increase intra-abdominal pressure (pregnancy, ascites, COPD, chronic
constipation, benign prostate hypertrophy) increase the risk of abdominal herniae

• Umbilical herniae are common in neonates (esp. of African descent) weak in the umbilical ring

• A congenital hernia: weakness in the abdominal wall with raised intra-abdominal pressure (e.g. coughing
or straining during defecation)

• Acquired umbilical herniae occur mostly in women and obese people are usually para-umbilical.

• Weakness in the anterior abdominal wall may be related to gaps (congenital, age-related, obesity-related,
surgery-related, trauma-related) in the fibres of the abdominal aponeuroses either in the midline or where
the aponeurosis meets the rectus sheath

• Abdominal hernias are usually enveloped by a sac of peritoneum (aka hernial sac)

• Femoral hernias (more common in women) below the inguinal ligament, when abdominal contents pass
through a naturally occurring weakness in the femoral canal. The bulk of the hernia lies beneath a line
corresponding to the inguinal ligament

Management

Initial management

• Give analgesia

• Raise the foot of the bed

• 20-30 minutes later - attempt to reduce the hernia

• If the hernia is reducible operative repair is usually carried out 24-48 hours later (next available list)

• If the hernia is irreducible the patient is sent for emergency surgery in order to prevent strangulation

• If complications have occurred (i.e. ischaemic damage to part of the bowel due to strangulation), the
surgeon will check the viability of the herniated organ, and resect it if necessary.

• Repair of a femoral hernia is either performed by suturing the inguinal ligament to the pectineal ligament
using strong non-absorbable sutures or by placing a mesh plug in the femoral ring (avoid any pressure on
the femoral vein).

Surgery
• Conventional surgery is based on apposition of the transversus abdominis and transversalis fascia and the
lateral rectus sheath to the inguinal ligament with sutures.
• Laparoscopic repair is usually reserved for recurrences and bilateral hernias. There is less postoperative
pain, full recovery is better, and return to work is faster However, the price is increased compared to the
 conventional approach, and there appears to be a higher number of serious complications of visceral
(especially bladder) and vascular injuries.
There are 2 approaches either the trans-abdominal pre-peritoneal (TAPP) or the totally extra-peritoneal (TEP)
procedure
• TAPP into the peritoneal cavity and places mesh through a peritoneal incision over possible hernia sites
• TEP mesh is used to seal the hernia from outside the peritoneum where the mesh becomes incorporated by
fibrous tissue (this is preferred)
Surgery can be performed on a day case basis and for 7 days afterwards the patient should avoid driving and lifting.
The patient should be able to resume normal activities over next 2-3 weeks, but can take up to 6 weeks to return to
work with a heavy job
A truss may be required where surgery is inadvisable or refused, but however it can be difficult for the patients to
manage and cannot be recommended as a definitive form of treatment.

Anatomy of inguinal canal

• Lies parallel to the inguinal

ligament

• In males contains spermatic

cord in females round
ligament, ilioinguinal nerve
in both sexes

Borders of the inguinal canal

• Anterior wall formed by

external oblique fascia

• Posterior wall transversalis

fascia and conjoint tendon
medially (common fascia of
int oblique and transversus
abdominis)
 • Roof internal oblique and transversus abdominis arching fibres

• Floor is the inguinal ligament

Economics of hernia repair

• Unlike the open method, laparoscopic surgery requires general anesthesia. It is usually more expensive and
consumes more O.R. time than open repair, carries a higher risk of complications, and has equivalent or
higher rates of recurrence compared to the open tension-free repairs.
• In the UK NICE (2004) evaluated the laparoscopic method and found that there is no difference in cost, as
the increased costs of operation (Laparoscopic method) are offset by the decreased recovery period
(Compared to open).
• Although, they did find that laparoscopic repair results in a more rapid recovery, and less pain in the first
few days. They found that lap repair has less risk of wound infection, less bleeding and less swelling after
surgery.

So open repair = Increased recovery time

Laparoscopic = Actual surgery is more expensive and takes longer, but shorter recovery time.
So currently, open repair is still widely used in the UK.

General complications of hernia repair

• Unexpected reaction to the anaesthetic
• Excessive bleeding
• Infection
• Rarely, blood or fluid will build up in the space left by the hernia.
• In men, painful swelling of the scrotum or testicles occasionally occurs. This may require further surgery.
• Very rarely, during surgery other tissues in the abdomen are damaged i.e. injury to the vas deferens, colon,
bladder Studies suggest that this is more likely if the operation is done using the laparoscopic method.
• There's a small chance of continuing pain or numbness in the groin area, caused by the handling of a nerve
during surgery, or by the pressure on the nerves by scar tissue that forms during healing.
• There's a chance the hernia may re-occur.

Costs of hernia repair

• Hernia repairs in a private hospital or clinic cost in the region of £1,400 to £2,700 inclusive of hospital
charges and consultant’s fees.
• Primary inguinal hernia surgery will cost around £1,500.
• Umbilical hernia repairs cost around £1,700

Consent for procedures

Outline consent (including model answer)

• The concept of consent represents the legal expression of the human right to have one’s autonomy respected
• The criteria for consent include:
o Competency to give consent i.e. mainly understanding the information, and basing a decision on it
o Adequately informed:
 About the proposed procedure
 About the possible impact on herself, and
 About the probabilities of such an impact.
o Voluntary decision; that is, being free of inducements or threats not directly related to the possible
benefits or burdens of treatment.
o Cannot consent to something that is immoral/contrary to public policy
• Consent is required if medical treatment is to be lawful, otherwise it is considered BATTERY (Offences
Against the Person Act of 1861).

Considerations as to whether to operate or not (model answer)

• The most important issue: the patient's consent or wishes – if she is competent to give it (if not, the surgeons
may proceed under the 'doctrine of necessity')
• If she is incompetent (e.g. unconscious), then the doctors should then consider the question of whether surgery
would benefit her (balance of likely benefits over likely harms) or would be futile.
• The decision about ‘futility’ will require judgements on the clinical condition of the patient, particularly
o about the probability of success (surviving the operation)
o about the patient's quality of life
• The presence of an advance directive or DNR in her medical notes.
• Degree of harm/ suffering from being put through surgical procedure

Reasons for not wanting to go for surgery (including model answer)

• Factors relating to health professionals:
o Failure to explain condition
o Failure to explain the procedure – what it is for; how it will be done; what it involves; impact of the surgery
in terms of time off work/recovery time/pain
o Failure to explain consequences of not having the procedure
o (Over-complicated treatment regimen - referring to compliance with medication only)
• Factors relating to patient:
o Refusal to accept that he is ill
o Refusal to believe that the procedure is necessary/effective
o Difficulty in fitting procedure into life – taking into consideration the recovery time
o Depression resulting in loss of motivation

Communication Skills

The process of the Calgary-Cambridge guide

1. Initiate the session:
• Establish initial rapport – greet patient nicely, introduce self, role, and nature of interview, demonstrates
respect and interest, and attends to patient’s physical comfort
• Obtain consent if necessary
• Identifies reasons for consultation – patient issues, listens, confirms lists and screens for further problems,
negotiates agenda taking both patient’s and physician’s needs into account
2. Gathering Information:
• Exploration of patient’s problems with encouragement (ICE) – verbal and non-verbal facilitation
• Open and closed questioning techniques, appropriately moving from open to closed – clarify statements;
concise and easily understood questions; avoid jargon
• Pick up cues
• Summarise to verify own understanding
3. Explanation
• Provide the correct amount and type of information – assess starting point, ask what the patient wants to
know, relates explanation to patient’s perspective (previously elicited ICEs)
• Give further explanation at appropriate times
 • Chunk and check - gives information in assimilatable chunks, checks for understanding, uses patient’s
response as a guide to how to proceed
• Achieve a shared understanding by incorporating the patient’s perspective
4. Planning and shared decision making
• Shares own thinking as appropriate: ideas, thought processes and dilemmas
• Explores management options
• Involves patient: offers suggestions and choices rather than directives, encourages patient to contribute
their own ideas, suggestions  negotiates a mutually acceptable plan
• Checks with patient – for acceptance of plan and if concerns have been addressed
5. Closing the session
• Contracts with patient re next steps for patient and physician
• Safety nets, explaining possible unexpected outcomes, what to do if plan is not working, when and how to
seek help
• Summarises session briefly and clarifies plan of care
• Final check that patient agrees and is comfortable with plan and asks if any corrections, questions or other
issues

The key points of a good consultation

• Providing Structure
o Making organisation overt
o Summarises at the end of a specific line of inquiry to confirm understanding before moving on to the
next section
o Progresses from one section to another using signposting, transitional statements; includes rationale
for next section
• Building Relationship
o Using appropriate non-verbal behaviour - eye contact, facial expression, posture, position
&movement, vocal cues e.g. rate, volume, intonation
o If reads, writes notes or uses computer, does in a manner that does not interfere with dialogue or
rapport
o Demonstrates appropriate confidence
• Developing rapport
o Accepts legitimacy of patient’s views and feelings; is not judgmental
o Uses empathy to communicate understanding and appreciation of the patient’s feelings or predicament,
overtly acknowledges patient's views and feelings
o Provides support: expresses concern, understanding, willingness to help; acknowledges coping efforts
and appropriate self care; offers partnership
o Deals sensitively with embarrassing and disturbing topics and physical pain, including when
associated with physical examination
• Involves the patient
o Shares thinking with patient to encourage patient’s involvement